Kaposi's Sarcoma [KS] is a complex neoplasm with significant morbidity especially in men, and prominent in HIV-1 positive homosexual men who experience a high [>30%] occurrence. Since 1988, the Program Director has pioneered etiologic studies of KS, identifying the importance of the HIV-1 induced inflammatory milieu in the proliferation of target spindle cells, and the effects of a pregnancy-associated factor, termed hCG-associated factor (HAF) with potent anti-KS effects. Building upon these initial studies the current Program Project extends these findings by integrating pathogenesis and pre-clinical treatment research to implement a series of carefully integrated strategies. This program grant is dedicated to a comprehensive study of the pathogenesis of KS and the novel mechanisms of HAF. Our overall hypothesis is that KS has its onset in microvascular inflammatory lesions which results from the action of inflammatory cytokines togethers with the HIV-1 Tat protein. The newly discovered human herpes virus 8 (HHV8) harbors human homologue genes which code for factors that also impact this milieu and thus may synergize this proliferative process. Our recent discovery of a characteristic translocation involving chromosome 3:14 involving the FHIT gene provides a novel molecular strategy for defining the malignant cells of KS and the role of this suppressor gene in carcinogenesis. The general aims of this program are to: 1) establish the mechanisms of action of HAF; 2) identify and characterize the active moiety; 3) investigate the role of some HHV8 genes, which are homologs of cellular cytokines and the chemokine receptor, in KS pathogenesis; and, 4) establish the extent to which a specific chromosomal alteration on the short arm of chromosome 3 is diagnostic or prognostic of the stage(s) of KS. This program is composed of four highly interactive projects [Projects 1-4] led by experienced investigators. These projects are supported by close association with an Animal Core [Core B] and a Virus and Cell Biology Core [Core C]. All projects and cores operate under an Administrative Core [Core A].